1. Field of the Invention
This invention relates to novel cyclosporin analogs, methods for their production, and their use for treating immunoregulatory and respiratory diseases, disorders, and conditions.
2. Description of the State of the Art
Cyclosporin, originally called cyclosporin A, is the main component of a large family of cyclic undecapeptides. This family, originally isolated from cultures of Cylindrocarpon lucidum Booth and Tolypocladium Gams, is produced as secondary fungal metabolites. Cyclosporin, initially pursued for its antifungal activities, is an effective immunosuppressant, acting primarily through T-lymphocytes via inhibition of the phosphatase calcineurin. Cyclosporin reduces the production of a range of cytokines, inhibiting the activation of various cell types, including those involved in cell-mediated immunity. Due to these properties, cyclosporin remains a first line therapy in the transplantation field.
Cyclosporin has the following structure:

which can also be represented by the following structure showing the amino acid residues referred to by abbreviations in accordance with conventional practice:

In addition to its wide use for preventing and treating organ transplant rejection, cyclosporin has been evaluated in a large range of disorders linked to immunoregulatory dysfunction and respiratory diseases. Cyclosporin, along with other calcineurin inhibitors, has been used for the treatment of nephritic syndrome, active Crohn's disease, acute ocular Behget syndrome, endogenous uveitis, psoriasis, atopic dermatitis, rheumatoid arthritis, aplastic anemia, primary biliary cirrhosis, celiac disease and other immunoregulatory diseases. Limited evidence suggests cyclosporin is effective in patients with intractable pyoderma gangrenosum, polymyostitis/dermatomyositis or severe, corticosteroid-dependent asthma (D. Faulds, K. L. Goa, and P. Benfield; Drug Evaluation, 1993, 45:953 and P. J. Wahab, et al., Aliment Pharmacol. Ther., 2000, 14:767). The effect of cyclosporin and other calcineurin inhibitors on inflammatory cells and their mediators make it a promising therapy for asthma, COPD (chronic obstructive pulmonary disease), idiopathic pulmonary fibrosis, and other lung diseases. Treatment of these disorders with cyclosporin is limited to patients with severe disease that are either refractory or hypersensitive to standard treatments due to adverse events including, but not limited to, hypertrichosis, gingival hyperplasia, neurological effects, gastrointestinal effects, and renal dysfunction. Chronic cyclosporin treatment requires frequent renal function monitoring due to increased incidence of kidney failure.
The mechanism of toxicity of calcineurin inhibitors such as cyclosporin has been related to the mechanism of immunosuppression (F. J. Dumont, et al., J. Exp. Med., 1992, 176:751–760). This strong link between cyclosporin's mechanism of action and many cyclosporin-induced toxicities has presented a significant challenge to medicinal chemists who have tried to improve the therapeutic index of cyclosporin through chemical modification. Indeed, these efforts, to date, have failed to separate cyclosporin efficacy from its toxicity. Segregation of efficacy and toxicity of cyclosporin analogs might still be possible by altering a compound's distribution or metabolism (N. H. Signal, et. al., J. Exp. Med., 1991, 173:619). The systemic toxicity of cyclosporin A therefore limits its use for the treatment of certain diseases. It is therefore desirable to find compounds for the treatment of immunoregulatory and respiratory diseases with improved systemic efficacy and safety.